tbuckley/cabot-search huggingface dataset:
Safety, pharmacokinetics, and clinical activity of OBI-3424, an AKR1C3-activated prodrug, in patients with advanced or metastatic solid tumors: A phase 1 dose-escalation study.
Authors: Apostolia Maria Tsimberidou, Claire F. Verschraegen, Pei Hsu, Tillman E. Pearce
Journal: Journal of Clinical Oncology (2022)

3030 Background: OBI-3424 is a novel nitrogen mustard prodrug that can be selectively converted in the presence of the AKR1C3 enzyme into the bis-alkylating agent OBI-2660, which forms intra- and inter-strand DNA crosslinks resulting in cell death. This selective mode of activation distinguishes OBI-3424 from traditional alkylating agents, and potentially improves the safety profile and antitumor activity against chemo- and radio-resistant tumors. We conducted a first-in-human, phase 1, dose-escalation study of OBI-3424 monotherapy in patients with advanced solid tumors (NCT03592264). Methods: OBI-3424 was administered intravenously at doses of 1, 2, 4, 6, 8, or 12 mg/m 2 (Days 1 and 8 every 21 days, Schedule A) or 8, 10, 12, or 14 mg/m 2 (Day 1 every 21 days, Schedule B). A “3+3” design was used for dose escalation. Patients received study treatment until disease progression, unacceptable toxicity, or up to 2 years of treatment. Results: Overall, 39 adult patients were treated. In patients receiving Schedule A, the maximum tolerated dose (MTD) of OBI-3424 was determined to be 8 mg/m 2 . Dose limiting toxicities (DLTs) were reported at the 12 mg/m 2 dose level, including thrombocytopenia (Grade 3-4, 5 of 6 patients) and anemia (Grade 3-4, 5 of 6 patients). Platelet count nadirs were noted on Day 15 or Day 22. These cytopenias led to dose modification and resulted in protocol amendment (Schedule B). In Schedule B, the MTD was not reached at the maximum dose tested (14 mg/m 2 ). Grade 3 or higher anemia was noted in 3 of 6 patients treated at 14 mg/m 2 ; the recommended phase 2 dose (RP2D) is 12 mg/m 2 (Day 1 every 21 days). Treatment-related AEs (TRAEs) were noted in 82% (32/39) of patients. The most common TRAEs were anemia (64%), thrombocytopenia (51%), nausea (26%), and fatigue (21%). No patient had a fatal TRAE, 49% had ≥Grade 3 TRAEs, including 3 patients who had serious TRAEs. OBI-3424 showed linear pharmacokinetics from 1 to 14 mg/m 2 , with minimal accumulation after repeated dosing. A retrospective validated automated immunohistochemistry assessment indicated that 27% of patients had high AKR1C3 staining (H-score ≥135). Best confirmed response was stable disease in 21 patients (54%). Conclusions: We completed the dose-escalation portion of the study. The RP2D was determined to be 12 mg/m 2 once every 3 weeks. OBI-3424 was well tolerated. Dose-dependent, non-cumulative thrombocytopenia and anemia were dose limiting. We are currently enrolling patients with pancreatic cancer and other tumor types with overexpression of AKR1C3 (H-score ≥135) in the expansion phase of the study. Clinical trial information: NCT03592264.
Elderberry extract inhibits tumour necrosis factor induced monocyte adhesion to endothelial cells via modulation of the NF-κB pathway
Authors: J Festa, H Singh, A Hussain, M Da Boit
Journal: Cardiovascular Research (2022)

Abstract Funding Acknowledgements Type of funding sources: Other. Main funding source(s): De Montfort PhD funded scholarship scheme Introduction During the early stages of atherosclerosis, monocytes attach to endothelial cells (EC) before differentiating into macrophages causing the accumulation of foam cells and plaque growth. NF-κB and vascular cell adhesion molecule 1 (VCAM-1) are some of the main mediators in EC that are involved in the monocyte adhesion process. Elderberry extract (EE) are rich in anthocyanins a subclass polyphenol with vascular-protective properties. Purpose The main of aim of this study is to examine if EE can prevent TNF-α induced inflammation and monocyte adherence to EC. Methods Primary Human Umbilical Vein Endothelial Cells (HUVEC) were pre-treated for 1-h and stimulated with or without TNF-α 10 ng/ml for western blot. Cell lysates from the treated cells were then subjected to Western blotting and probed for total and phospho-NF-κB. For monocyte adherence cells were pre-treated for 24-h, then stimulated with/or without TNF-α 10 ng/ml for 24-h. Fluorescently labelled THP-1 cells were then added to the HUVECs for an additional 30 minutes, and samples were measured in a fluorescence plate reader. Cells were put through flow cytometry for measuring reactive oxygen species (ROS) using DCFHFDA assay or VCAM-1 levels using Anti-CD106. Results An increase in ROS production and NF-κB phosphorylation was found after stimulation TNF-α 10 ng/ml (p = 0.01). However, cells pre-incubated with EE (50 μg/ml) for 1-hour before TNF-α stimulation caused a reduction in ROS as well as inhibition of NF-κB phosphorylation (p &amp;lt; 0.01). TNF-α 10 ng/ml increased the monocyte adherence to the HUVECs by a 2-fold although, EE prevented TNF-α monocyte adherence (mean value, 589.7 vs 408 p = 0.0033). This was associated with suppressed VCAM-1 expression found in the EE pre-treatment with TNF-α (p = 0.02). Discussion Our Preliminary data demonstrates that EE, can prevent monocytes binding onto EC potentially by inhibiting TNF-α induced NF-κB and VCAM-1 levels. Our findings postulate that NF-κB and VCAM-1 could be the direct link for targeting the prevention of monocyte adherence to EC, although this would need confirmation by blocking key cellular signalling pathways to confirm its role. This preliminary data suggests that EE and potentially other polyphenols could be a useful strategy for targeting the initial stages of atherosclerosis.
Mobocertinib (TAK-788) in <i>EGFR</i> exon 20 insertion (ex20ins)+ metastatic non–small cell lung cancer (mNSCLC): Treatment (tx) beyond progressive disease (PD) in platinum-pretreated patients (pts) with and without intracranial PD.
Authors: Pasi A. Janne, Suresh S. Ramalingam, James Chih-Hsin Yang, Gregory J. Riely, Veronica Bunn, Shu Jin, Caicun Zhou, D. Ross Camidge
Journal: Journal of Clinical Oncology (2022)

9099 Background: Mobocertinib is a potent, irreversible, oral tyrosine kinase inhibitor selectively targeting EGFR ex20ins in NSCLC. Mobocertinib demonstrated clinical efficacy in 114 platinum-pretreated pts (PPP) with EGFR ex20ins+ mNSCLC in a phase 1/2 study. Methods: In this study (NCT02716116), pts with ECOG status 0–1 and ≥1 prior therapy line for locally advanced/metastatic EGFR ex20ins+ NSCLC received mobocertinib 160 mg QD. Pts were allowed to continue tx beyond PD at the discretion of the investigator (INV) if evidence of clinical benefit existed. We present data on continuation of mobocertinib tx beyond PD in the PPP cohort by site of first PD (brain vs extracranial). Results: At the November 1, 2020, data cutoff, among PPP (n=114; median age 60 y, 66% female, 60% Asian), 59% had ≥2 prior systemic anticancer lines; 35% had baseline brain metastases (Zhou C, et al. JAMA Oncol. 2021;7(12):e214761. doi:10.1001/jamaoncol.2021). Confirmed objective response rate (cORR) per independent review committee (IRC) was 28%; median duration of response was 17.5 mo. IRC-assessed cORR was 34% among PPP with no baseline brain metastases versus 18% among PPP with baseline brain metastases (Zhou C, et al. JAMA Oncol. 2021;7(12):e214761. doi:10.1001/jamaoncol.2021); median progression-free survival was 9.2 and 3.7 mo, respectively. Per INV assessment, 64 pts had PD. Duration of mobocertinib tx beyond PD is summarized in the Table. Among pts with first site of PD in brain per INV (n=21), 17 (81%) pts remained on mobocertinib tx beyond PD; 7 (33%) received radiotherapy to brain and remained on mobocertinib tx, of whom 3 pts remained on mobocertinib tx for ≥6 mo and 1 pt for ≥12 mo. Among pts with first site of PD outside the brain per INV (n=43), 28 (65%) pts continued tx beyond PD and 4 (9%) pts remained on mobocertinib tx for ≥6 mo. Conclusions: These results suggest that mobocertinib may have limited intracranial activity given the high frequency of first PD in brain (25%) and numerically lower IRC-assessed cORR in pts with baseline brain metastases. Per INV assessment, pts may derive ongoing systemic benefit from mobocertinib. Duration of time to next progression based on local therapy continues to be investigated. Clinical trial information: NCT02716116. [Table: see text]
TBIO-06. Study of cell free DNA extracted from CSF enables molecular classification of embryonal brain tumors
Authors: Chicard Mathieu, Yasmine Iddir, Julien Masliah-Planchon, Valérie Combaret, Alexandra Saint-Charles, Sylvain Baulande, Olivier Delattre, Joshua Waterfall, Franck Bourdeaut, Gudrun Schleiermacher
Journal: Neuro-Oncology (2022)

Abstract Liquid biopsies are revolutionary tools to detect tumour-specific genetic alterations in body fluids. Here, we assess whether the circulating tumor DNA (ctDNA) in Cerebral Spinal Fluid (CSF) could be used for the tumor genetic profiling of pediatric embryonal brain tumors (EBT). Cell free DNA extracted from CSF from 4-5 lumbar puncture droplets from patients with Medulloblastoma (n=18), ATRT (n=3), ETMR(n=1), FOXR2 EBT (n=2) or other pediatric EBT (n=1) (cfDNA mean quantity 48 ng/ml ; range 5.6 - 442 ng/ml) and matched genomic DNA from primary tumors were sequenced by WES (Illumina 100PE) using Nimblegen Medexome Capture. SNVs/mutations were called using GATK-UnifiedGenotyper, GATK-HaplotypeCaller and Samtools. Copy Number profiles were generated with CNVkits. 10/13 cfDNA WES yielded satisfactory depth (&amp;gt;10x). A mean of 466 (range 93-945) SNVs were detected in the primary tumor and 474 (range 18-922) in the CSF. A mean of 416 (range 18-872) commons SNVs were observed between the cfDNA and the primary tumor, comprising classical medulloblastoma genes such as SMO or MLL2. Interestingly, several SNVs were observed either in the tumor only (mean 50 ; range 3-115) or in CSF only (mean 58 ; range 0-148) suggesting a clonal heterogeneity. For 5 cases, Copy Number profiles were also available, allowing the detection of MYCN amplification or 19q13 miRNA cluster amplification. Altogether, we demonstrate the feasibility of WES on CSF with a low input of ctDNA. These results may pave the way for new tumor monitoring tools.
Outcomes and prognostic assessment of post-transplant lymphoproliferative disorder.
Authors: Hira Shaikh, Zulfa Omer, Roman Jandarov, Aaron Delman, Tahir Latif
Journal: Journal of Clinical Oncology (2022)

e19548 Background: Post-transplant lymphoproliferative disorder (PTLD) is the most common malignancy after solid organ transplantation (SOT) in adults, apart from skin cancer. It is a serious and potentially fatal complication of chronic immunosuppression in SOT recipients. Methods: Institutional electronic health record (EHR), Epic was queried for PTLD patients evaluated at the University of Cincinnati Cancer Center 1991 - 2020. Relationships between clinical characteristics and time from diagnosis to death were assessed using t-test and ANOVA, with SAS 9.4. Overall survival (OS) was evaluated by Kaplan Meier estimates, from the date of PTLD diagnosis to death or last follow-up. Results: Sixty patients were identified with PTLD in the study period. A higher proportion of males (65%) and Caucasians (92%) was noted. The most common type of transplants were kidney (40%) and liver (32%). The median time from transplant to PTLD was 7.3 y and the median age at diagnosis was 54.5 y. The majority had monomorphic PTLD (60%) and presented as Stage IV (25%) or with end-organ dysfunction (67%). Most had extranodal involvement (67%), with GI (23%) being the most frequently involved site. EBV was positive in 32%. Immunosuppression was changed in 75% of the patients and most received rituximab-chemotherapy (55%), with two-thirds achieving a response. The 2-year OS was 55%. Gender (males 44%, females 14%; p = 0.0216), transplant type (lung 67%, liver 53%, kidney 21%, kidney-pancreas 0%; p = 0.0183) and treatment response (CR 20%, PR 29%, no response 100%; p = 0.0003) were significantly associated with mortality. Median time from PTLD diagnosis to death was 5.2 mo, being significantly shorter in liver transplant recipients (p &lt; 0.0001), those managed by observation only (p &lt; 0.0001) or with end-organ dysfunction at diagnosis (0.0072). A similar trend was noted in males, non-Caucasians, HLA-mismatch, and polymorphic PTLD, but this was statistically nonsignificant. Conclusions: This investigation highlights the prognostic risk factors of PTLD, that could be helpful in the management of the patients and guiding future research.[Table: see text]
Patterns of care in Medicaid-enrollees with recurrent or metastatic cervical cancer.
Authors: Charles A. Leath, Jessica Nysenbaum, Anthony Fiori, Jie Ting, Jenny Zhang, Nathan Pauly
Journal: Journal of Clinical Oncology (2022)

e17525 Background: Cervical cancer remains a disease with high unmet need, and a large proportion of patients are insured through Medicaid (̃30%). Previous real-world studies demonstrated significant variability in treatments for recurrent or metastatic cervical cancer (r/mCC) patients following doublet chemotherapy ± bevacizumab, despite the 2018 approval of pembrolizumab in PD-L1+ r/mCC. As r/mCC treatment landscape continues to evolve, there is a need to understand current real-world unmet need among Medicaid r/mCC patients. This study aims to evaluate treatment patterns and healthcare resource utilization (HCRU) among Medicaid-insured r/mCC patients. Methods: This is a retrospective analysis of nationwide Medicaid claims to assess patient characteristics, treatment patterns, and HCRU among r/mCC patients between 2016-2019 (most recent Medicaid data available). First line treatment (1L) for r/mCC was identified as the first administration of systemic therapy without concomitant radiation or surgery. Patient characteristics, treatment patterns, and HCRU were characterized by line of therapy. Results: A total of 2,741 adult females initiated systemic treatment for r/mCC between 2016–2019, mean age was 52.8 (SD = 12.8), and most patients were enrolled in comprehensive managed care plans (58%). Over 41% (N = 1,145) had evidence of second line treatment (2L), with over one third (N = 385) of those also having evidence of third line treatment (3L). Consistent with treatment guidelines, the majority (61%) of 1L regimens were doublet chemotherapy ± bevacizumab. In contrast, no clear standard of care was observed among patients receiving 2L or 3L therapy. Notably, immunotherapy accounted for 22% of treatment regimens in 2L/3L overall, with its use increasing significantly over time (&lt; 6% in 2016 to 41% in 2019; p-value &lt; 0.001); however, despite availability of immunotherapy, most patients did not remain on treatment for a prolonged duration (immunotherapy median duration 2.2 months vs. 2.5 months for non-immunotherapy, p-value = 0.9). Across all HCRU measures (inpatient admissions, outpatient visits, emergency visits, and pharmacy claims), 2L/3L patients had less utilization per patient, compared with 1L patients. Conclusions: There was no clear standard of care for 2L+ r/mCC patients enrolled in Medicaid treated between 2016-2019. Although immunotherapy use is increasing, there is still high medical unmet need based on short durations of treatment and poor historical outcomes. New therapies should provide meaningful clinical benefit without significant increase in HCRU.
MEDB-45. Functional genomics identifies epigenetic regulators as novel therapeutic targets for sonic hedgehog medulloblastoma
Authors: Foteini Tsiami, Federica Piccioni, David Root, Pratiti Bandopadhayay, Rosalind Segal, Ghazaleh Tabatabai, Daniel Merk
Journal: Neuro-Oncology (2022)

Abstract Medulloblastoma (MB) is among the most common malignant childhood brain tumors that comprises a group of four molecularly distinct diseases. A significant proportion of these tumors is characterized by aberrant activation of the canonical sonic hedgehog (SHH) signaling pathway. Although small-molecule inhibitors targeting Smoothened (SMO) have proven a promising treatment approach for SHH-MB subgroup, primary or acquired resistance impedes its clinical efficacy. Therefore, novel targeted approaches are urgently needed to improve therapeutic strategies for this tumor entity. Here, we conducted a genome-wide CRISPR/Cas9 knockout screen in a murine and a human SHH-MB cell line, SMB21 and DAOY, respectively, in order to decipher tumor-specific genetic dependencies. Our data demonstrate that SMB21 cells highly depend on positive regulators of the SHH pathway, such as Smo and Gli1 for their survival, as opposed to DAOY cells, suggesting that the latter does not represent a faithful model of SHH-MB. Members of the epigenetic machinery such as Dnmt1 and Smarca5 scored strongly as SMB21-context specific essentialities. Pharmacologically, we show that DNMT1 inhibition is efficacious at clinically relevant concentrations against SMO inhibitor- sensitive, as well as resistant SHH-MB cell lines, indicating novel therapeutic avenues for SHH-MB. By performing RNA sequencing of SMB21 cells, we identified early and late changes in global gene expression induced by DNMT1 inhibition, including decreased expression of mediators of SHH signaling, such as Gli1 and Gli2. Of note, gene set enrichment analysis revealed that DNMT1 inhibition downregulates top gene sets associated with cell cycle progression, corroborating the screening results that Dnmt1 is essential for SMB21 proliferation. Further global DNA methylation profiling in SMB cells will help to define the molecular basis of sensitivity to DNMT1 inhibitors in SHH-MB. Summarizing, our data highlight the potential of inhibitors targeting epigenetic regulators in SMO inhibitor- sensitive and resistant MB for more efficacious treatment options.
MODL-11. The tumor suppressor CREBBP and the oncogene MYCN cooperate to induce malignant brain tumors in mice
Authors: Schoof Melanie, Gefion Dorothea Epplen, Carolin Walter, Annika Ballast, Dörthe Holdhof, Carolin Göbel, Sina Neyazi, Thomas Albert, Kornelius Kerl, Ulrich Schüller
Journal: Neuro-Oncology (2022)

Abstract CREBBP (cAMP response element-binding protein binding protein) and MYCN (v-myc avian myelocytomatosis viral oncogene neuroblastoma derived homolog), two essential proteins in central nervous system development that are described to be genetically altered in the same brain tumor entities, such as high grade glioma or medulloblastoma. Therefore, we hypothesized that alterations in both genes cooperate to induce brain tumor formation. In order to investigate molecular mechanisms and potential tumor formation, we established a novel mouse model combining a deletion of Crebbp with an overexpression of MYCN in neural stem cells (hGFAP-cre::CrebbpFl/Fl::lsl-MYCN). The animals developed highly aggressive forebrain tumors with 75 % penetrance already detectable in seven-day old mice, leading to tumor-related death within eight months. Although tumors mostly developed in the olfactory bulb region, we hypothesized that these tumors develop from subventricular stem cells that migrate into the olfactory bulb, where they settle and establish large solid tumors. In order to test this hypothesis, we analyzed neural stem cells (NSCs) derived from our mouse model. Compared to control cells, NSCs from transgenic mice have a significantly increased cell viability and proliferation in vitro and did not undergo full glial differentiation. In order to gain further insights into the cellular origin and biology of the tumors, we finally employed single cell RNA sequencing. Apart from a high intratumoral heterogeneity within the tumor cell population, data comparison with non-neoplastic CNS cell populations revealed a high similarity with transit-amplifying NSCs of the subventricular zone. Together, we were able to show the oncogenic potential of a combined loss of Crebbp and aberrant expression of MYCN in neural stem cells. This novel mouse model will be an important tool for understanding tumor-driving mechanisms and a valuable model for preclinical testing and will thereby help to improve patient care.
DDEL-02. Intra-arterial Delivery for Novel Combinatorial Chemotherapies in Choroid Plexus Carcinoma
Authors: Brice Martin, Tyler Garman, Madeline Laramee, Amy Wang, Natalie Hagen, Nadia Dahmane, Craig Thomas, Mark Souweidane
Journal: Neuro-Oncology (2022)

Abstract Choroid plexus carcinoma (CPC) is a rare infantile brain tumor with an aggressive clinical course that often leaves children with debilitating side effects due to aggressive and toxic chemotherapies. New delivery routes such as intra-arterial (IA) route are being explored to limit toxicity and improve efficacy. To identify novel compounds that may be used in this context, we conducted a high-throughput screen (HTS) informing on the cytotoxicity of 2454 compounds, including some currently approved for IA in other brain tumors, that identified multiple active drugs on a human primary CPC cell line. Key molecular targets previously identified in CPC literature such as mTOR, PDGFR, ATR, CDK, FGFR1 and PI3K were enriched relative to other targets in the screen. Importantly, a combination screen with a wide variety of targets revealed multiple synergistic combinations. We examined two key combinations (topotecan/elimusertib and melphalan/elimusertib) based on mechanistic alignment and translational potential through extended in vitro validation and transcriptome analyses. Pharmacokinetic assays established increased drug brain penetrance with IA delivery when compared with intravenous delivery. Ultimately, a single intra-arterial administration of melphalan combined with systemic administration of elimusertib led to a significant increased survival in a CPC genetic mouse model. This study underscores the efficacy of IA delivery and identifies a promising therapeutic option for the treatment of CPC.